Human Genetics

, Volume 127, Issue 5, pp 525–535

Genetic variation in the IL7RA/IL7 pathway increases multiple sclerosis susceptibility

  • Rebecca L. Zuvich
  • Jacob L. McCauley
  • Jorge R. Oksenberg
  • Stephen J. Sawcer
  • Philip L. De Jager
  • International Multiple Sclerosis Genetics Consortium
  • Cristin Aubin
  • Anne H. Cross
  • Laura Piccio
  • Neelum T. Aggarwal
  • Denis Evans
  • David A. Hafler
  • Alastair Compston
  • Stephen L. Hauser
  • Margaret A. Pericak-Vance
  • Jonathan L. Haines
Original Investigation

Abstract

Multiple sclerosis (MS) is characterized as an autoimmune demyelinating disease. Numerous family studies have confirmed a strong genetic component underlying its etiology. After several decades of frustrating research, the advent and application of affordable genotyping of dense SNP maps in large data sets has ushered in a new era in which rapid progress is being made in our understanding of the genetics underlying many complex traits. For MS, one of the first discoveries to emerge in this new era was the association with rs6897932[T244I] in the interleukin-7 receptor alpha chain (IL7RA) gene (Gregory et al. in Nat Genet 39(9):1083–1091, 2007; International Multiple Sclerosis Genetics Consortium in N Engl J Med 357(9):851–862, 2007; Lundmark in Nat Genet 39(9):1108–1113, 2007), a discovery that was accompanied by functional data that suggest this variant is likely to be causative rather than a surrogate proxy (Gregory et al. in Nat Genet 39(9):1083–1091, 2007). We hypothesized that variations in other genes functionally related to IL7RA might also influence MS. We investigated this hypothesis by examining genes in the extended biological pathway related to IL7RA to identify novel associations. We identified 73 genes with putative functional relationships to IL7RA and subsequently genotyped 7,865 SNPs in and around these genes using an Illumina Infinium BeadChip assay. Using 2,961 case–control data sets, two of the gene regions examined, IL7 and SOCS1, had significantly associated single-nucleotide polymorphisms (SNPs) that further replicated in an independent case–control data set (4,831 samples) with joint p values as high as 8.29 × 10−6 and 3.48 × 10−7, respectively, exceeding the threshold for experiment-wise significance. Our results also implicate two additional novel gene regions that are likely to be associated with MS: PRKCE with p values reaching 3.47 × 10−4, and BCL2 with p values reaching 4.32 × 10−4. The TYK2 gene, which also emerged in our analysis, has recently been associated with MS (Ban et al. 2009). These results help to further delineate the genetic architecture of MS and validate our pathway approach as an effective method to identify novel associations in a complex disease.

Supplementary material

439_2010_789_MOESM1_ESM.doc (671 kb)
Supplementary material 1 (DOC 671 kb)
439_2010_789_MOESM2_ESM.doc (87 kb)
Supplementary material 2 (DOC 87 kb)

References

  1. Ansel KM et al (2006) Regulation of Th2 differentiation and Il4 locus accessibility. Annu Rev Immunol 24:607–656CrossRefPubMedGoogle Scholar
  2. Australia and New Zealand Multiple Sclerosis Genetics Consortium (2009) Genome-wide association study identifies new multiple sclerosis susceptibility loci on chromosome 12 and 20. Nat Genet 41(7):824–828CrossRefGoogle Scholar
  3. Ban M et al (2009) Replication analysis identifies TYK2 as a multiple sclerosis susceptibility factor. Eur J Hum Genet 17(10):1309–1313CrossRefPubMedGoogle Scholar
  4. Baranzini SE et al (2009a) Pathway and network-based analysis of genome-wide association studies in multiple sclerosis. Hum Mol Genet 18(11):2078–2090CrossRefPubMedGoogle Scholar
  5. Baranzini SE, Wang J, Gibson RA (2009b) Genome-wide association analysis of susceptibility and clinical phenotype in multiple sclerosis. Hum Mol Genet 18(4):767–778CrossRefPubMedGoogle Scholar
  6. Barrett JC et al (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21(2):263–265CrossRefPubMedGoogle Scholar
  7. Bertrams J, Kuwert E (1972) HL-A antigen frequencies in multiple sclerosis. Significant increase of HL-A3, HL-A10 and W5, and decrease of HL-A12. Eur J Neurol 7(74):78Google Scholar
  8. Compston A, Coles A (2002) Multiple sclerosis. Lancet 359(9313):1221–1231CrossRefPubMedGoogle Scholar
  9. De Jager PL et al (2009) Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci. Nat Genet 41(7):776–782CrossRefPubMedGoogle Scholar
  10. Ebers GC, Sadovnick AD, Risch NJ (1995) A genetic basis for familial aggregation in multiple sclerosis. Canadian Collaborative Study Group [see comments]. Nature 377(6545):150–151CrossRefPubMedGoogle Scholar
  11. Ebers GC et al (1996) A full genome search in multiple sclerosis. Nat Genet 13(4):472–476CrossRefPubMedGoogle Scholar
  12. Fry TJ, Mackall CL (2005) The many faces of IL-7: from lymphopoiesis to peripheral T cell maintenance. J Immunol 174(11):6571–6576PubMedGoogle Scholar
  13. Gabriel S, Ziaugra L, Tabbaa D (2009) SNP genotyping using the Sequenom MassARRAY iPLEX platform. Curr Protoc Hum Genet, Chapter 2:UnitGoogle Scholar
  14. Goverman J (2009) Autoimmune T cell responses in the central nervous system. Nat Rev Immunol 9(6):393–407CrossRefPubMedGoogle Scholar
  15. Gregory SG et al (2007) Interleukin 7 receptor alpha chain (IL7R) shows allelic and functional association with multiple sclerosis. Nat Genet 39(9):1083–1091CrossRefPubMedGoogle Scholar
  16. Haines JL et al (1996) A complete genomic screen for multiple sclerosis underscores a role for the major histocompatability complex. The Multiple Sclerosis Genetics Group. Nat Genet 13(4):469–471CrossRefPubMedGoogle Scholar
  17. Hauser SL, Goodkin DE (1998) Multiple sclerosis and other demyelinating diseases. In: Fauci AD et al (eds) Harrison’s principle of internal medicine. McGraw Hill, New York, pp 2409–2419Google Scholar
  18. Hauser MA et al (2003) Genomic convergence: identifying candidate genes for Parkinson’s disease by combining serial analysis of gene expression and genetic linkage. Hum Mol Genet 12(6):671–677CrossRefPubMedGoogle Scholar
  19. Hennah W et al (2007) Families with the risk allele of DISC1 reveal a link between schizophrenia and another component of the same molecular pathway, NDE1. Hum Mol Genet 16(5):453–462CrossRefPubMedGoogle Scholar
  20. Hirschhorn JN et al (2002) A comprehensive review of genetic association studies. Genet Med 4(2):45–61CrossRefPubMedGoogle Scholar
  21. Hofmeister R et al (1999) Interleukin-7: physiological roles and mechanisms of action. Cytokine Growth Factor Rev 10(1):41–60CrossRefPubMedGoogle Scholar
  22. International Multiple Sclerosis Genetics Consortium (2005) A high-density screen for linkage in multiple sclerosis. Am J Hum Genet 77:454–467CrossRefGoogle Scholar
  23. International Multiple Sclerosis Genetics Consortium (2007) Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med 357(9):851–862CrossRefGoogle Scholar
  24. International Multiple Sclerosis Genetics Consortium (2009a) The expanding genetic overlap between multiple sclerosis and type I diabetes. Genes Immun 10(1):11–14CrossRefGoogle Scholar
  25. International Multiple Sclerosis Genetics Consortium (2009b) Comprehensive follow-up of the first genome-wide association study of multiple sclerosis identifies KIF21B and TMEM39A as susceptibility loci. Hum Mol Genet [Epub ahead of print]Google Scholar
  26. Jiang Q et al (2004) Distinct regions of the interleukin-7 receptor regulate different Bcl2 family members. Mol Cell Biol 24(14):6501–6513CrossRefPubMedGoogle Scholar
  27. Jiang Q et al (2005) Cell biology of IL-7, a key lymphotrophin. Cytokine Growth Factor Rev 16(4–5):513–533CrossRefPubMedGoogle Scholar
  28. Kisseleva T et al (2002) Signaling through the JAK/STAT pathway, recent advances and future challenges. Gene 285(1–2):1–24CrossRefPubMedGoogle Scholar
  29. Kumpfel T et al (2008) Multiple sclerosis and the TNFRSF1A R92Q mutation: clinical characteristics of 21 cases. Neurology 71(22):1812–1820CrossRefPubMedGoogle Scholar
  30. Kuokkanen S et al (1997) Genomewide scan of multiple sclerosis in Finnish multiplex families. Am J Hum Genet 61:1379–1387CrossRefPubMedGoogle Scholar
  31. Lundmark F (2007) Variation in interleukin 7 receptor alpha chain (IL7R) influences risk of multiple sclerosis. Nat Genet 39(9):1108–1113CrossRefPubMedGoogle Scholar
  32. McDonald WI et al (2001) Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 50(1):121–127CrossRefPubMedGoogle Scholar
  33. McGovern DP et al (2009) Genetic epistasis of IL23/IL17 pathway genes in Crohn’s disease. Inflamm Bowel Dis 15(6):883–889CrossRefPubMedGoogle Scholar
  34. Motsinger AA et al (2007) Complex gene–gene interactions in multiple sclerosis: a multifactorial approach reveals associations with inflammatory genes. Neurogenetics 8(1):11–20CrossRefPubMedGoogle Scholar
  35. Mumford GL et al (1994) The British Isles survey of multiple sclerosis in twins. Neurology 44(11):15Google Scholar
  36. Naito S et al (1972) Multiple sclerosis: association with HL-A3. Tissue Antigens 2(1):1–4PubMedCrossRefGoogle Scholar
  37. O’Shea JJ (2004) Targeting the Jak/STAT pathway for immunosuppression. Ann Rheum Dis 63(Suppl 2):ii67–ii71CrossRefPubMedGoogle Scholar
  38. Ritchie MD et al (2001) Multifactor-dimensionality reduction reveals high-order interactions among estrogen-metabolism genes in sporadic breast cancer. Am J Hum Genet 69(1):138–147CrossRefPubMedGoogle Scholar
  39. Robertson NP et al (1996) Age-adjusted recurrence risks for relatives of patients with multiple sclerosis. Brain 119(Pt 2):449–455CrossRefPubMedGoogle Scholar
  40. Sadovnick AD, Ebers GC (1995) Genetics of multiple sclerosis. Neurol Clin 13:99–118PubMedGoogle Scholar
  41. Sadovnick AD et al (1993) A population-based study of multiple sclerosis in twins: update. Annal Neurol 33:281–285CrossRefPubMedGoogle Scholar
  42. Sadovnick AD et al (1996) Evidence for genetic basis of multiple sclerosis. Lancet 347(1728):1730Google Scholar
  43. Sawcer S (2008) The complex genetics of multiple sclerosis: pitfalls and prospects. Brain 131(Pt 12):3118–3131CrossRefPubMedGoogle Scholar
  44. Sawcer S et al (1996) A genome screen in multiple sclerosis reveals susceptibility loci on chromosome 6p21 and 17q22. Nat Genet 13:464–468CrossRefPubMedGoogle Scholar
  45. Sexton DP et al (2007) The Whole-genome Association Study Pipeline (WASP): a comprehensive tool for large-scale association studies. Am J Hum Genet 57:413SGoogle Scholar
  46. Shirai Y, Adachi N, Saito N (2008) Protein kinase Cepsilon: function in neurons. FEBS J. 275(16):3988–3994CrossRefPubMedGoogle Scholar
  47. Steemers FJ et al (2006) Whole-genome genotyping with the single-base extension assay. Nat. Methods 3(1):31–33CrossRefPubMedGoogle Scholar
  48. Transatlantic Multiple Sclerosis Genetics Cooperative (2001) A meta-analysis of genomic screens in multiple sclerosis. Mult Scler 7(1):3–11CrossRefGoogle Scholar
  49. Wang WY et al (2005) Genome-wide association studies: theoretical and practical concerns. Nat Rev Genet 6(2):109–118CrossRefPubMedGoogle Scholar
  50. Wellcome Trust Case Control Consortium (2007) Genome-wide association study of 14, 000 cases of seven common diseases and 3, 000 shared controls. Nature 447(7145):661–678CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Rebecca L. Zuvich
    • 1
  • Jacob L. McCauley
    • 2
  • Jorge R. Oksenberg
    • 3
    • 4
  • Stephen J. Sawcer
    • 5
  • Philip L. De Jager
    • 6
    • 7
    • 12
    • 13
  • International Multiple Sclerosis Genetics Consortium
  • Cristin Aubin
    • 7
    • 13
  • Anne H. Cross
    • 8
  • Laura Piccio
    • 8
  • Neelum T. Aggarwal
    • 9
    • 10
  • Denis Evans
    • 9
    • 10
  • David A. Hafler
    • 7
    • 11
    • 13
  • Alastair Compston
    • 5
  • Stephen L. Hauser
    • 3
  • Margaret A. Pericak-Vance
    • 2
  • Jonathan L. Haines
    • 1
  1. 1.Center for Human Genetics ResearchVanderbilt University Medical CenterNashvilleUSA
  2. 2.John P. Hussman Institute for Human Genomics, Miller School of MedicineUniversity of MiamiMiamiUSA
  3. 3.Department of Neurology, School of MedicineUniversity of CaliforniaSan FranciscoUSA
  4. 4.Institute for Human Genetics, School of MedicineUniversity of CaliforniaSan FranciscoUSA
  5. 5.Department of Clinical Neurosciences, Addenbrooke’s HospitalUniversity of CambridgeCambridgeUK
  6. 6.Program in Translational NeuroPsychiatric Genomics, Department of NeurologyBrigham and Women’s HospitalBostonUSA
  7. 7.Program in Medical and Population GeneticsBroad Institute of Harvard UniversityCambridgeUSA
  8. 8.Department of NeurologyWashington UniversitySt. LouisUSA
  9. 9.Rush Alzheimer Disease Center, Department of Neurological SciencesRush UniversityChicagoUSA
  10. 10.Rush Institute for Healthy AgingRush UniversityChicagoUSA
  11. 11.Department of NeurologyYale School of MedicineNew HavenUSA
  12. 12.Harvard Medical SchoolBostonUSA
  13. 13.Massachusetts Institute of TechnologyCambridgeUSA

Personalised recommendations